Our initial studies have centered on S-adenosylmethionine (AdoMet) metabolism in cultured murine erythroleukemic cells (MELC). We had previously observed that AdoMet levels in MELC varied as a function of the growth phase of the cell. Maximal levels were found in exponential phase cells, declining to minimal levels in stationary phase. This suggested the possibility of cell cyclespecific fluctuations in this important metabolite. When MELC were synchronized using a double thymidine block, this fluctuation was confirmed. Maximal AdoMet levels of 180 attomoles/cell occurred in early S phase about 1 hour before peak thymidine incorporation. AdoMet declined to a minimum of 70 attomoles/cell at mitosis. Additional studies on MELC involve the induction of hemoglobin synthesis by various agents. There is a rationale for AdoMet involvement in this process since changes in DNA methylation and polyamine metabolism have been shown by many other laboratories. We have found that the inducers dimethyl sulfoxide, butyrate, hexamethylene bisacetamide ethionine and ouabain all lower AdoMet levels. This apparently occurs because transport of methionine, glucose and K+ is impaired. Since methionine, ATP (from glucose metabolism) and K+ are all required by methionine adenosyltransferase for AdoMet synthesis, decreases in these three components result in lower intracellular AdoMet. This provides a unifying hypothesis for MELC induction since other inducers are known to inhibit DNA methylases directly. Present objectives are: (1) To determine the biochemical basis for the cell cycle-specific fluctuation of AdoMet in MELC. This will involve studies of the rate of synthesis of AdoMet as well as its utilization for transmethylation and polyamine biosynthesis, all as a function of cell cycle stage. (2) To determine the rates of synthesis and utilization of AdoMet in transmethylation and polyamine synthesis in hepatocytes from normal, malignant and regenerating rat liver.